Description of the condition
Worldwide, nearly 225,000 women are diagnosed with ovarian cancer each year making it the eighth most common cancer in women. The estimated risk of getting the disease is approximately 1% in developed countries (Europe, Northern America, Australia/New Zealand and Japan) and 0.5% in the rest of the world (GLOBOCAN 2008).
Ovarian cancer usually has a silent onset and, initially, inconspicuous progression. Symptoms are characteristically non-specific and include abdominal swelling and pain, early satiety and increased urinary urgency and frequency (NICE 2011). This absence of a clear clinical profile results in most women being diagnosed with advanced-stage disease (FIGO III and IV; FIGO 2009) making ovarian cancer the deadliest of all gynaecological cancers with five-year relative survival rates of only 37% and 54% in Europe and America, respectively (EUROCARE-4 2009; SEER 2007). Importantly, however, if women are diagnosed at FIGO stage I, they have a 90% chance of surviving the following five years (SEER 2007).
The need to improve the detection of early disease was recognised over 30 years ago and led to the development of screening protocols using vaginal examination, measurement of serum CA125 levels and ultrasonography (Campbell 1989; Jacobs 1988). However, while studies using refined diagnostic techniques, such as transvaginal ultrasound, are still underway (Menon 2009), it is not yet clear if the implementation of a screening programme would lower mortality rates and benefit affected women. Around 90% of ovarian malignancies are epithelial ovarian cancers and other types include germ cell, stromal cell and Müllerian tumours (SEER 2007). Primary diagnostic tests for ovarian cancer are the measurement of serum CA125 levels and ultrasonography. If disease is suspected women undergo explorative laparotomy, when the tumour is histologically classified and staged and all macroscopic disease is removed (NICE 2011).
Further standard treatment is disease-dependent. Women presenting with low-grade stage I tumours might not undergo chemotherapy, while high-grade stage I and all other stages receive intravenous platinum-based chemotherapy in combination with paclitaxel (NICE 2011). Carboplatin is usually favoured over cisplatin because it is less toxic but has equivalent efficacy (NICE 2003). Surgery and standard adjuvant chemotherapy have a response rate of 70% to 80%, however, 55% to 75% of responders relapse within two years of treatment completion (NICE 2003).
Description of the intervention
Doxorubicin hydrochloride is a cytotoxic drug that has been available since the 1960s and belongs to the anthracycline family (EMA 2010). It was originally used in the first-line treatment of ovarian cancer in the 1970s, when in vitro experiments showed a dose-response relationship in ovarian cancer cell lines; activity against epithelial ovarian cancer was subsequently proven in clinical trials (A'Hern 1995; OCMP 1991; Ozols 1980). Despite its potent antineoplastic activity, the clinical use of doxorubicin has been limited by its associated side effects, in particular haematological toxicity and irreversible cardiac damage. Pegylated liposomal doxorubicin (PLD) is a formulation of liposomal doxorubicin that is coated in polyethylene glycol (PEG), which reduces the rate at which the active drug is broken down (Gabizon 2001) and makes it less toxic to heart muscle.
In the UK, PLD is currently licensed for the treatment of advanced ovarian cancer in women for whom platinum-based chemotherapy has failed (EMA 2010). In these women, PLD may be given intravenously at a dose of 50 mg/m² once every four weeks for six cycles if tolerated and if the disease does not progress (EMA 2010). However, recent trials have employed lower doses (e.g. CALYPSO 2010; 30 mg/m² every four weeks) to reduce drug-related adverse effects. The main toxicities associated with PLD are nausea, palmar-plantar erythema (redness and soreness of palms of hands and soles of feet), stomatitis and myelosuppression (Janssen-Cilag 2011).
Although single-agent PLD treatment is usually employed in platinum-resistant disease (NICE 2011), PLD in combination with platinum (CALYPSO 2010; HeCOG 2010) has been shown to be a good alternative to carboplatin/paclitaxel treatment in platinum-sensitive relapsed disease. Compared with standard carboplatin/paclitaxel treatment, the carboplatin/PLD regimen may be better tolerated: in CALYPSO 2010, significantly more women experienced complete hair loss, hypersensitivity reactions and neuropathies in the paclitaxel arm compared with the PLD arm, and women in the paclitaxel arm were more likely to discontinue treatment. Since PLD in combination with carboplatin is a good alternative to carboplatin/paclitaxel for relapsed ovarian cancer, carboplatin/PLD may represent a good alternative to the current standard carboplatin/paclitaxel for first-line chemotherapy.
How the intervention might work
Anthracyclines function by interacting with DNA, adversely affecting all cell functions that rely on DNA. Furthermore, they interact with cell membranes, altering their functions and generating hydrogen peroxide and hydroxy radicals which are highly destructive to cells (Zunino 2002). The special PEG coating of PLD represents a hydrophilic barrier, protecting the liposomes from detection by the reticuloendothelial system and increasing the time that the active drug remains in circulation (Gabizon 1997; Gabizon 2001). Moreover, the size of the liposomes prevents them from entering tissues with tight capillary junctions, such as the heart and gastrointestinal tract, reducing toxicity, while leading to accumulation and increased drug concentrations in the tumour (Waterhouse 2001), resulting in increased efficacy.
Why it is important to do this review
PLD is a novel formulation of a proven chemotherapeutic agent, with an improved efficacy and safety profile. There is good evidence to support its use in the treatment of relapsed ovarian cancer in combination with carboplatin in platinum-sensitive disease, and as a single agent in platinum-resistant disease. This represents a strong rationale for testing PLD in the first-line setting. Following the completion of a large randomised controlled trial (RCT) of PLD/carboplatin for first-line treatment of ovarian cancer (MITO-2 2011), we consider it important to review the evidence relating to PLD administration, before or after primary cytoreductive surgery, as initial chemotherapy for newly diagnosed ovarian cancer.